Novel benzofuran derivatives and therapeutic agents containing them

ABSTRACT

Benzofuran derivatives of the formula I ##STR1## where R 1  to R 5  and X have the meanings stated in the description, and therapeutic agents containing these derivatives.

The present invention relates to novel benzofuran derivatives of the formula I and therapeutic agents which contain these derivatives and are used for the treatment of cardiovascular disorders, coronary heart diseases, vasospasms and hypertension.

German Laid-Open Applications DOS 2,235,941 and DOS 2,238,115 describe benzofuran derivatives which have a powerful in vitro calcium-antagonistic activity but have only weak enteral activity.

We have found, surprisingly, that the benzofuran derivatives of the formula ##STR2## where R¹ and R² independently of one another are each hydrogen, alkyl or phenylalkyl where alkyl in each case is of 1 to 4 carbon atoms, R³, R^(3') and R^(3") are each hydrogen, benzyloxy, fluorine, chlorine, bromine, hydroxyl or C₁₋₆ -alkoxy, or are each amine which is monosubstituted or disubstituted by C₁ -C₄ -alkyl or C₁ -C₄ -acyl, or are each nitro, hydroxymethyl or C₁ -C₄ -alkyl, and two adjacent radicals R³ and R^(3') together may form the radical --CH═CH--NH--, R⁴ and R⁵ independently of one another are each hydrogen, C₁ -C₄ -alkyl or phenylalkyl where alkyl is of 1 to 4 carbon atoms and the phenyl nucleus may be monosubstituted or disubstituted by fluorine, chlorine, bromine, C₁ -C₄ -alkoxy, unsubstituted or mono-or di-C₁ -C₄ -alkyl-substituted amine or nitro, or R⁴ and R⁵ together form a 3-membered to 6-membered chain which may contain an oxygen or nitrogen atom and may be bonded to a benzene ring which in turn may be substituted by fluorine, chlorine, bromine, C₁ -C₄ -alkoxy, unsubstituted or mono- or di-C₁ -C₄ -alkyl-substituted amine or nitro, X is --CO--CH═CH--, --CO--CH₂ --CH₂ -- or --CHOH--CH₂ --CH₂ --, n is 2 or 3 and ##STR3## is a single or double bond, with the proviso that if R¹ and R² are simultaneously methyl, R⁴ can only be hydrogen or alkyl and R⁵ can only be unsubstituted or substituted phenylalkyl or R⁴ and R⁵ together form a 3-membered to 6-membered chain which may contain an oxygen or nitrogen atom and is bonded to an unsubstituted or substituted benzene ring, have substantially higher oral availability while retaining the calcium-antagonistic activity.

The novel compounds of the formula I can in principle be prepared by the processes as described in German Patent Application P 37 10 469.1.

The compounds of the general formula I where X is --CO--CH₂ CH₂ can be prepared from the compounds of the formula I in which X is --CO--CH═CH-- by catalytic hydrogenation of the double bond by methods known from the literature, as described in, for example, R. N. Rylander, Catalytic Hydrogenation over Pt Metals, Acad. Press, New York, page 282, 1967. Particularly suitable catalysts are metal catalysts, such as palladium on carbon or Raney nickel in alcohol.

The compounds of the general formula I in which X is --CH(OH)--CH₂ CH₂ can be prepared by reduction of the compounds of the general formula I where X is --CO--CH₂ CH₂, with a metal hydride by a conventional method, as described in Houben-Weyl, Methoden der org. Chemie, 4th edition, G. Thieme Verlag Stuttgart 1984, volume 6/1b, page 145. Examples of suitable metal hydrides are LiAlH₄ in ethers and NaBH₄ in alcohols, such as ethanol or isopropanol.

These compounds can also be prepared from the compounds of the formula I where X is --CO--CH═CH-- by catalytic hydrogenation as described in Houben-Weyl, vol. 6/1b, page 61, or by reduction with a metal hydride, as described in Houben-Weyl, 4th edition, (1981), vol. 4/1d, page 297 and in German Laid-Open Application DOS 2,235,941.

The compounds of the formula I where X is --CO--CH═CH-- are synthesized from the acetophenones of the formula III by condensation with aromatic aldehydes by known methods, as described in, for example, Org. Reactions vol. 16, page 1 et seq., John Wiley Publishers, New York 1968. Examples of suitable condensing agents are alkali metal hydroxides in aqueous alcoholic solution.

The compounds of the formula III where R¹ and R² are each CH₃ can be obtained by alkylation of the o-hydroxyacetophenone khellinone II (J. Amer. Chem. Soc. 72 (1950), 1613) with a haloalkylamine, as described in Chimie Therapeutique 4 (1973), 475 and German Patent Application P 37 10 469.1. The alkylation of II ##STR4## can also be carried out with aminoalcohols under conditions of the Mitsunobu method (Synth. 1981, 1).

The compounds of the formula III where R¹ and R² is not CH₃ can be prepared by alkylation of the hydroxyacetophenones IV ##STR5## by a conventional method of phenol synthesis (Houben-Weyl vol. VI/3, page 49 et seq.). For example, the alkylation can be carried out with an alkyl halide using an alkali metal carbonate as the base in acetone as a solvent, or using a metal hydride in an aprotic solvent, such as dimethylformamide or tetrahydrofuran.

The compounds IV are obtainable via hydrogenolysis of the benzyl ether V by a known method (Houben-Weyl vol. 4/1c, page 385 et seq.). The debenzylation is preferably carried out at room temperature in order to avoid hydrogenation of the furan ring.

The compounds V are synthesized from the hydroxyacetophenones VI by the process described for the preparation of III (where R¹ and R² are each CH₃).

The hydroxyacetophenone VI is prepared by alkaline ring cleavage of the pyrone VII by the method described in German Patent Application P 37 10 469.1. ##STR6##

The compounds of the general formula I in which the furan ring is hydrogenated are synthesized in a similar manner, a suitable intermediate, for example II, being converted into the corresponding dihydrobenzofuran derivative by a conventional method of catalytic hydrogenation.

The hydrogenation is preferably carried out at slightly elevated temperatures of from 20° to 100° C. using Pd or Pt as catalyst.

The novel compounds of the formula I in which X is CHOH--CH₂ CH₂ possess a center of chirality and are obtained as racemates, which can be resolved into the optically active antipodes by a known method, for example by formation of diastereomeric salts with optically active acids or dibenzoyltartaric acid, camphor-10-sulfonic acid or ditolytartaric acid.

If necessary, the resulting novel compounds can be converted into addition salts with a physiologically tolerated acid. A list of conventional physiologically tolerated acids is given in Fortschritte der Arzbneimittelforschung 1966, Birkhauser Verlag, vol. 10, pages 224-285, Germany, Switzerland.

The addition salts with acid are, as a rule, obtained in a conventional manner by mixing the free base or a solution thereof with the corresponding acid or a solution thereof in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, or a lower ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or an ether, such as diethyl ether, tetrahydrofuran or dioxane. To improve deposition of crystals, mixtures of the stated solvents may be used. Moreover, pharmaceutically acceptable aqueous solutions of acid addition compounds of the aminopropanol derivatives of the formula I can be prepared by dissolving the free bases in an aqueous acid solution.

The novel compounds (of the general formula I) and their physiologically tolerated addition salts with acids have useful pharmacological properties. They are highly active Ca antagonists and consequently produce in vitro relaxation of the blood vessels. They also reduce the arterial blood pressure in normotonic and hypertensive experimental animals. They are furthermore capable of protecting the myocardium from the loss of high-energy phosphates (e.g. adenosine triphosphate, ATP) which occurs during anoxic respiration, i.e. they have a cardioprotective action.

Because of the pronounced Ca-antagonistic action and the superior antihypertensive and cardioprotective action, the novel compounds are suitable for the enteral treatment of cardiovascular disorders, in particular coronary heart disease, and of vasospasms and hypertension.

The dose depends on the age, condition and weight of the patient and on the route of administration. As a rule, the daily dose of active compound is about 10-1000 mg per patient.

The novel compounds can be used in the conventional solid pharmaceutical enteral administration forms, for example as tablets, film tablets, capsules, powders, granules, coated tablets or suppositories. These are prepared in a conventional manner and to do so the active compounds can be mixed with the conventional pharmaceutical auxiliaries, such as tablet binders, fillers, preservatives, tablet disintegrators, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents and antioxidants (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms thus obtained normally contain the active compound in an amount of from 1 to 99% by weight.

The following method is used to demonstrate the pharmacological activity:

Antihypertensive action

The substances are administered orally to spontaneously hypertensive male Okamoto rats (SHR) weighing 270-380 g (5-10 animals per dose). The systolic blood pressure is determined prior to administration and 2 hours afterwards non-invasively at the tail of the rat with the aid of piezoelectric crystal transducers by a plethysmographic method. The dose which reduces the systolic blood pressure by 20% is determined as the ED 20%, the values for untreated control animals being taken into account.

                  TABLE                                                            ______________________________________                                         Blood pressure lowering doses (ED 20%, mg/kg) in                               conscious spontaneously hypertensive rats (SHR)                                               Antihypertensive                                                               activity SHR p.o.                                               Example          ED 20%   R.P.*                                                ______________________________________                                          1               5.0      17.2                                                  2               6.7      12.7                                                  3               21.5     4.0                                                   5               21.5     4.0                                                   7               5.5      15.6                                                  9               21.5     4.0                                                  18               13.1     6.5                                                  20               8.0      10.7                                                 21               12.6     6.8                                                  23               21.5     4.0                                                  25               25.7     3.3                                                  27               16.7     5.1                                                  Piprofurol       85.5     1                                                    ______________________________________                                          *Relative potency; Piprofurol = 1.0                                      

The results show that the orally administered novel substances have good hypotensive and antihypertensive actions.

EXAMPLES FOR THE PREPARATION OF THE STARTING COMPOUNDS 5-Acetyl-4,7-dimethoxy-6-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)propoxy]-benzofuran

39 g of 5-acetyl-6-hydroxy-4,7-dimethoxybenzofuran are refluxed with 40 g of 3-chloropropyl-(2-(3,4-dimethoxyphenyl)-ethyl)-methylamine in 250 ml of methyl ethyl ketone for 14 hours. The mixture is filtered, the solvent is stripped off and the oily residue is dissolved in dilute HCl. The aqueous phase is washed with ether, rendered alkaline with dilute sodium hydroxide solution and extracted with ether. Stripping off the solvent gives 45 g of crude oily product which is further reacted without purification.

4-Benzyloxy-9-methoxy-7-methylfuro[3,2-g]chromone

95 g of 4-hydroxy-9-methoxy-7-methfuro[3,2-g]chromone in 1000 ml of methyl ethyl ketone are refluxed with 100 g of benzyl bromide and 210 g of K₂ CO₃ for 15 hours. 1000 ml of CH₂ Cl₂ are added to the mixture, which is then filtered, and the solvent is distilled off. After treatment with petroleum ether, the residue gives 123 g of VII (where R¹ is CH₃) as a yellowish oil.

5-Acetyl-4-benzyloxy-6-hydroxy-7-methoxybenzofuran

113 g of VII (where R¹ is CH₃) are added a little at a time to a solution of 67 g of KOH in 1000 ml of water at 75° C. The mixture is refluxed for 3 hours and then cooled and filtered. The filtrate is acidified with 110 ml of concentrated hydrochloric acid, and the precipitated residue is filtered off under suction and dried to give 115 g of V (where R¹ is CH₃).

5-Acetyl-4-benzyloxy-7-methoxy-6-(2-N-piperidinoethoxy)-benzofuran

50 g of VI (where R¹ is CH₃) in 400 ml of methyl ethyl ketone are refluxed with 35 g of chloroethylpiperidine and 90 g of K₂ CO₃ for 5 hours. The mixture is filtered and the filtrate is evaporated down. The residue is partitioned between water and ether. 69 g of V (where R¹ is CH₃) are obtained as a yellowish oil.

5-Acetyl-4-hydroxy-7-methoxy-6-(2-N-piperidinoethoxy)-benzofuran

18.5 g of V (where R¹ is CH₃ and R³ and R⁴ together are pentamethylene) are dissolved in 150 ml of ethyl acetate and the solution is stirred with 1 g of Pd/C under atmospheric pressure at room temperature in a hydrogenation apparatus until the absorption of hydrogen has ended. The catalyst is filtered off and the filtrate is evaporated down. The residue gives 16 g of the desired product.

5-Acetyl-4-ethoxy-7-methoxy-(2-piperidinoethoxy)-benzofuran

3.3 g 5-Acetyl-4-hydroxy-7-methoxy-6-(2-piperidinoethoxy)-benzofuran in 2 ml of dimethylformamide are added dropwise to a suspension of 0.4 g of NaH (55% strength in liquid paraffin) in 10 ml of dimethylformamide at room temperature. The mixture is stirred for 30 minutes, after which 2.1 g of ethyl iodide are added. Stirring is continued overnight and the mixture is poured onto ice and extracted with ether. The ether phase is washed with water and evaporated down. The residue is partitioned between CH₂ Cl₂ and 1N HCl. The organic phase is dried and evaporated down to give 2.0 g of the hydrochloride and evaporated down to give 2.0 g of the hydrochloride of the desired compound.

The following are prepared in a similar manner:

5-acetyl-4-ethoxy-7-methoxy-6-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propoxy]-benzofuran, oil

5-acetyl-4,7-dimethoxy-6-[3-((2-(3-methoxyphenyl)-ethylmethylamino)-propoxy]-benzofuran, oil

5-acetyl-4-ethoxy-7-methoxy-6-[3-((2-(3-methoxyphenyl)-ethyl)-methylamino)-propoxy]-benzofuran, oil

5-acetyl-4,7-dimethoxy-6-[3-(4-(2-methoxyphenyl)-piperazinyl)-propoxy]-benzofuran, oil

5-acetyl-4,7-dimethoxy-6-[3-(4-phenylpiperidinyl)-propoxy]-benzofuran, oil

5-acetyl-2,3-dihydro-6-hydroxy-4,7-dimethoxybenzofuran

10 g of 5-acetyl-6-hydroxy-4,7-dimethoxybenzofuran in 100 ml of methanol are hydrogenated using 2 g of Pd/C (10%) at room temperature and under slightly superatmospheric pressure. When the absorption of hydrogen is complete, the mixture is filtered and the solvent is distilled off. 9.7 g of the desired product of melting point 100°-101° C. are obtained.

Examples of the preparation of the novel compounds:

EXAMPLE 1 1-[4,7-Dimethoxy-6-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propoxy]-benzofuran-5-yl]-3-(4-hydroxyphenyl)-propenone

8 g of acetyl-4,7-dimethoxy-6-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propoxy]-benzofuran and 4 g of 4-hydroxybenzaldehyde in 60 ml of ethanol and 20 g of concentrated sodium hydroxide solution were stirred overnight at room temperature. The mixture was poured onto ice, neutralized with dilute hydrochloric acid and extracted with CH₂ Cl₂. The organic phase was washed again with water, dried and evaporated down. The residue was dissolved in CH₂ Cl₂ using an equimolar amount of oxalic acid. The product was precipitated as the oxalate by adding ether.

Yield: 2.8 g, m.p. 60° C.

Examples 2 to 20 in Table 1 were synthesized in a similar manner. The structure of all compounds were ascertained by NMR spectroscopy.

EXAMPLE 21 1-[4-Ethoxy-7-methoxy-6-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propoxy)-benzofuran-5-yl]-3-(4-hydroxyphenyl)-propanone

15 of the chalkone from Example 2 in 200 ml of methanol were hydrogenated at room temperature using 1.5 g of Pd/C until the calculated amount of hydrogen had been absorbed. The solvent was distilled off and the residue was purified by chromatography. 2.1 g of oily product were obtained.

Examples 22 to 24 in Table 2 were synthesized in a similar manner.

EXAMPLE 25 1-(4-Ethoxy-7-methoxy-6-(2-N-piperidinoethoxy)benzofuran-5-yl)-3-(4-hydroxyphenyl)-propan-1-ol

3.7 g of NaBH₄ were added to 9 g of 1-(4-ethoxy-7-methoxy-6-(2-N-piperidinoethoxy)-benzofuran-5-yl)-3-(4-hydroxyphenyl)-propenone in 40 ml of ethanol and 7 g of pyridine at room temperature, and the mixture was refluxed for 5 hours. It was then poured onto iced water, neutralized with dilute HCl and extracted with CH₂ Cl₂. The organic phase was dried, the solvent was distilled off and the residue was chromatographed over silica gel (8:1 CH₂ Cl₂ /CH₃ OH).

3.7 g of product of melting point 132° C. were obtained.

The compounds in Table 3 were prepared in a similar manner.

                                      TABLE 1                                      __________________________________________________________________________      ##STR7##                                                                      Example                                                                             R.sup.1                                                                           R.sup.2                                                                           n NR.sup.4 R.sup.5   R.sup.3   R.sup.3'                                                                            R.sup.3"                                                                           Mp. [°C.]            __________________________________________________________________________      2   C.sub.2 H.sub.3                                                                   CH.sub.3                                                                          3                                                                                 ##STR8##          4-OH      H    H   oil                          3   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR9##          4-OH      H    H   oil                          4   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR10##         4-F       H    H   oil                          5   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR11##         H         H    H   oil                          6   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR12##         4-OH      H    H    67                          7   C.sub.2 H.sub.5                                                                   CH.sub.3                                                                          3                                                                                 ##STR13##         4-OH      H    H   oil                          8   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR14##                                                                                         ##STR15##                                                                               H    H   oil                          9   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR16##                                                                                         ##STR17##                                                                               H    H   oil                         10   C.sub.3 H.sub.7                                                                   CH.sub.3                                                                          3                                                                                 ##STR18##         4-OH      H    H   oil                         11   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR19##         4-OH,     3-OCH.sub.3                                                                         H   oil                         12   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR20##         3-OH      H    H   oil                         13   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR21##         4-NHCOCH.sub.3                                                                           H    H   oil                         14   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR22##         4-OH      H    H   158                         15   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR23##         4-OH      H    H   170                         16   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR24##         4-OH      H    H   160                         17   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR25##         3-Cl      5-Cl 4-OH                                                                               185                         18   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR26##         4-NHCHCH-3 (fused pyrrole)                                                                    H    70                         19   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR27##         4-OH, 3-CH.sub.2 OH                                                                           H    89                         20                                                                                   ##STR28##                                    oil                         __________________________________________________________________________

                                      TABLE 2                                      __________________________________________________________________________      ##STR29##                                                                     Example                                                                             R.sup.1                                                                           R.sup.2                                                                           n NR.sup.4 R.sup.5   R.sup.3                                                                            Mp. [°C.]                           __________________________________________________________________________     22   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR30##         4-OH                                                                               oil                                        23   C.sub.2 H.sub.5                                                                   CH.sub.3                                                                          3                                                                                 ##STR31##         4-OH                                                                               oil                                        24   CH.sub.3                                                                          CH.sub.3                                                                          3                                                                                 ##STR32##         H   oil                                        __________________________________________________________________________

                                      TABLE 3                                      __________________________________________________________________________      ##STR33##                                                                     Example                                                                             R.sup.1                                                                             R.sup.2                                                                           n NR.sup.4 R.sup.5   R.sup.3                                                                              Mp. [°C.]                       __________________________________________________________________________     25   C.sub.2 H.sub.5                                                                     CH.sub.3                                                                          2                                                                                 ##STR34##         4-OH  132                                    26   C.sub.6 H.sub.5 CH.sub.2                                                            CH.sub.3                                                                          2                                                                                 ##STR35##         4-OH  140                                    27   CH.sub.3                                                                            CH.sub.3                                                                          3                                                                                 ##STR36##         H     oil                                    28   C.sub.2 H.sub.5                                                                     CH.sub.3                                                                          2                                                                                 ##STR37##         4-N(CH.sub.3).sub.2                                                                  139 (fumarate)                         29   C.sub.3 H.sub.7                                                                     CH.sub.3                                                                          2                                                                                 ##STR38##         4-OH  122                                    30   CH.sub.3                                                                            CH.sub.3                                                                          3                                                                                 ##STR39##         4-OH  oil                                    31   CH.sub.3                                                                            CH.sub.3                                                                          3                                                                                 ##STR40##         H     oil                                    32   CH.sub.3                                                                            CH.sub.3                                                                          3                                                                                 ##STR41##         4-OH  oil                                    33   CH.sub.3                                                                            CH.sub.3                                                                          3                                                                                 ##STR42##         4-F   oil                                    __________________________________________________________________________ 

We claim:
 1. A benzofuran compound of the formula ##STR43## wherein R¹ and R² independently of one another are each alkyl or phenylalkyl where alkyl in each case is of 1 to 4 carbon atoms, R³, R^(3') and R^(3") are each hydrogen, benzyloxy, fluorine, chlorine, bromine, hydroxyl or C₁₋₆ -alkoxy, or are each amine which is monosubstituted or disubstituted by C₁ -C₄ -alkyl or C₁ -C₄ -acyl, or are each nitro, hydroxymethyl or C₁ -C₄ -alkyl, and two adjacent radicals R³ and R^(3') together may form the radical --CH═CH--NH--, R⁴ is C₁ -C₄ -alkyl and R⁵ is phenylalkyl where alkyl is of 1 to 4 carbon atoms and the phenyl nucleus is unsubstituted or monosubstituted or disubstituted by C₁ -C₄ -alkoxy, X is --CO--CH═CH--, --CO--CH₂ --CH₂ -- or --CHOH--CH₂ --CH₂ --, n is 2 or 3 and ##STR44## is a single or double bond.
 2. A therapeutic pharmaceutical composition for enteral use for the treatment of coronary heart disease, vasospasms and hypertension, which, in addition to a pharmaceutically acceptable carrier, contains an effective calcium-antagonistic amount of a benzofuran compound of the formula I as claimed in claim
 1. 3. A therapeutic pharmaceutical composition for enternal use which contains, in addition to a pharmaceutically acceptable carrier, from 10 to 1000 mg of a benzofuran compound of the formula I as claimed in claim 1 per individual dose.
 4. A method of treating coronary heart disease, vasospasms and hypertension in a subject in need thereof, which comprises administering to the subject an effective calcium-antagonistic amount of a benzofuran compound of the formula I as claimed in claim
 1. 